The field of the subject invention is mammalian genes associated with susceptibility to tumors.
There has been considerable interest in the development of a method for identifying mammalian cell genes whose concurrent homozygous inactivation de novo leads to a defined phenotype, where multiple alleles of a gene have been inactivated and where it is easy to confirm that the inactivation results in a phenotype distinguishable from the wild-type. One use of this method is the identification of genes involved in tumor susceptibility.
Tumor susceptibility genes may be oncogenes, which are typically upregulated in tumor cells, or tumor suppressor genes, which are down-regulated or absent in tumor cells Malignancies may arise when a tumor suppressor is lost and/or an oncogene is inappropriately activated. When such mutations occur in somatic cells, they result in the growth of sporadic tumors. Familial predisposition to cancer may occur when there is a mutation, such as loss of an allele encoding a tumor suppressor gene, present in the germline DNA of an individual. In the best characterized familial cancer syndromes, the primary mutation is a loss of function consistent with viability, but resulting in neoplastic change consequent to the acquisition of a second somatic mutation at the same locus.
Extensive studies of the early-onset breast cancer families have led to the recent identification of two candidate breast cancer suppressor genes, BRCA1 and BRCA2. Although frequent mutations of BRCA1 or BRCA2 have been demonstrated in familial early onset breast cancer, this type of cancer represents only about 5-10% of all breast malignancies, and the possible role(s) of BRCA1 and BRCA2 in the remaining 90-95% of sporadic breast cancers has not been determined.
Deletion and loss of heterozygosity (LOH) of markers in human chromosome band 11p15 have been shown in a variety of human cancers, including lung cancer, testicular cancer and male germ cell tumor, stomach cancer, Wilms"" tumor, ovarian cancer, bladder cancer, myeloid leukemia, malignant astrocytomas and other primitive neuroectodermal tumors, and infantile tumors of adrenal and liver. About 30% of sporadic breast carcinomas show a LOH in this region. Since LOH is believed to indicate inactivation of a tumor suppressor gene at the location where LOH occurs, the frequent LOH found at 11p15 in a variety of human cancers suggests the presence of either a cluster of tumor suppressor genes or a single pleiotropic gene in this region.
The clinical importance of these cancers makes the identification of this putative tumor suppressor gene of great interest for diagnosis, therapy, and drug screening.
Relevant Literature
Lemke et al. (1993) Glia 7:263-271 describes loss of function mutations engineered through the expression of antisense RNA from previously cloned genes and through the insertional inactivation of the Po gene, by homologous recombination in embryonic stem cells, and the generation of Po-deficient mice. Kamano et al. (1990) Leukemia Res. 10:831-839; van der Krol et al. (1988) Biotechnigues 6:958; Katsuki et al. (1988) Science 241:593-595; Owens et al. (1991) Development 112:639-649, and Owens et al. (1991) Neuron 7:565-575 describe changes in cell phenotype associated with the expression of antisense RNAs in different cell types. Giese et al. (1992) Cell 71:565-576 describes the inactivation of both copies of a gene in a transgenic mouse.
Studies of LOH in Wilms"" tumors identified a tumor suppressor locus at 11p15, for example see Dowdy et al. (1991) Science 254:293-295. Two familial breast cancer genes have been previously described, BRCA1 in Miki et al. (1994) Science 266.66-71, and BRCA2 in Wooster et al. (1995) Nature 378:789-792.
The interaction of stathmin with a coiled coil domain is described in Sobel (1991) Trends Biochem. Sci. 16:301-305.
Mammalian tumor susceptibility genes and methods for their identification are provided, including the complete nucleotide sequences of human TSG101 and mouse tsg101 cDNA. Deletions in TSG101 are associated with the occurrence of human cancers, for example breast carcinomas. The cancers may be familial, having as a component of risk an inherited genetic predisposition, or may be sporadic. The TSG101 nucleic acid compositions find use in identifying homologous or related proteins and the DNA sequences encoding such proteins; in producing compositions that modulate the expression or function of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer, identification of cell type based on expression, and the like. The DNA is further used as a diagnostic for a genetic predisposition to cancer, and to identify specific cancers having mutations in this gene.